Afatinib (1) – Giotrif®

• Clinical trials
  • The G-BA’s assessment is therefore based on the results of the LUX-Lung 3 trial. This was a multicentre, randomised, open-label Phase III trial. The study included previously untreated adult patients with lung adenocarcinoma (stage IIIB or IV) with activating EGFR mutations and an ECOG performance status of 0 or 1 at the start of the study. Patients were randomised in a 2:1 ratio to either an intervention group, which received afatinib, or a control group, which received cisplatin in combination with pemetrexed.

1a) Previously untreated patients with an ECOG performance status of 0 or 1 – patient group with the EGFR Del19 mutation

• For previously untreated patients with an ECOG performance status of 0 or 1 and the EGFR Del19 mutation, there is an indication of considerable additional benefit compared with the appropriate comparator therapy, cisplatin in combination with pemetrexed.
• The G-BA classifies the extent of the additional benefit of afatinib as considerable, based on the criteria set out in Section 5(7) of the AM-NutzenV, taking into account the severity of the disease and the therapeutic objective in the treatment of the disease. Compared with the appropriate comparator therapy of cisplatin in combination with pemetrexed, there is, in accordance with Section 5(7) in conjunction with § 2(3) of the AM-NutzenV, this represents a significant improvement in treatment-related benefit not previously achieved, as a moderate prolongation of survival (endpoint: overall survival) is achieved.
• The probability of the additional benefit is classified as an indication.
• mortality
  • Subgroup effects were observed for both data sets depending on EGFR mutation status (Del19, L858R, other mutations) (interaction tests: 1st data set: p = 0.033; 2nd data cut-off: p = 0.002). Therefore, the results from these patient populations are used to assess the additional benefit.
  • For the second data cut-off, in the patient population with the Del19 EGFR mutation, the median overall survival in the intervention arm was 31.57 months versus 21.13 months in the control arm (HR 0.55, 95% CI [0.36; 0.85]; p = 0.006).
• Morbidity – Progression-free survival (PFS)
  • At the time of the final PFS analysis (9 February 2012), the median PFS in the overall population was 11.1 months in the intervention arm versus 6.9 months in the control arm (HR = 0.58; 95% CI [0.43; 0.78]; p = 0.0004).
  • In the patient population with the EGFR Del19 mutation, the median PFS in the intervention arm was 13.7 months versus 5.55 months in the control arm (HR = 0.28, 95% CI [0.18; 0.44]; p < 0.0001).
• Morbidity – Dyspnoea
  • For the endpoint of dyspnoea, differences in favour of afatinib were observed with both questionnaires and for both operationalisations of the symptom.
  • In the EGFR Del19/L858R patient population, the proportion of patients with an improvement in symptoms was 42.6% in the intervention arm versus 21.9% in the control arm (QLQ-LC13; p = 0.002), and 45.6% in the intervention arm versus 27.1% in the control arm (QLQ-C30; p = 0.005). The proportion of patients with a worsening of symptoms was 47.1% in the intervention arm versus 58.7% in the control arm (QLQ-LC13; p < 0.001), and 33.3% in the intervention arm versus 50% in the control arm (QLQ-C30; p < 0.001).
• Morbidity – Cough
  • For the endpoint of cough, statistically significant differences in favour of afatinib were observed in the overall population. An improvement in symptoms was observed in 55.5% of patients in the intervention arm versus 36.2% of patients in the control arm (p = 0.003).
• Morbidity – pain (arm/shoulder)
  • For the endpoint of pain (arm/shoulder), a statistically significant difference in favour of afatinib was observed in the overall population: An improvement in symptoms was observed in 30.3% of patients in the intervention arm compared with 17.8% of patients in the control arm (p = 0.022).
• Morbidity – pain (chest)
  • For the endpoint ‘pain (chest)’, a statistically significant difference in favour of afatinib was observed in the overall population: The proportion of patients with a worsening of symptoms was 34.3% in the intervention arm versus 39.1% in the control arm (p = 0.023).
• Quality of life – Physical functioning (EORTC QLQ-C30)
  • In the patient population with the EGFR Del19 mutation, the proportion of patients showing an improvement in physical functioning was 27.1% in the intervention arm versus 8.9% in the control arm (p = 0.015). The proportion of patients with a deterioration in physical functioning was 50.4% in the intervention arm versus 68.4% in the control arm (p < 0.001).
• Side effects
  • The desired effects of afatinib are accompanied by adverse events (AEs). However, a comparison of side effects between the study arms is complicated by significant differences in the duration of follow-up.
  • Based on the unadjusted proportions, there were no significant differences between the study arms in the proportions of patients experiencing at least one adverse event, at least one serious adverse event, at least one AE of CTCAE grade 3 or 4, or at least one adverse event leading to discontinuation of the study.
  • With regard to common severe side effects (side effects of CTCAE grade ≥ 3 occurring in ≥ 5 % of patients in at least one study arm), different treatment-specific patterns were observed in the side effect profiles between the two treatment groups. Minor rates were observed in the intervention arm compared with the control arm for fatigue (2.2% versus 9.9%), neutropenia (0.9% versus 16.2%) and leucopenia (0.4% versus 8.1%). Higher rates in the intervention arm compared with the control arm were observed for diarrhoea (14.8% versus 1.8%), rash (13.1% versus 0%) and nail changes (11.4% versus 0%).
  • Overall, with regard to the assessment of additional benefit, the side effects do not indicate either an advantage or a disadvantage for afatinib.
• Conclusion
  • When the results on mortality, morbidity, quality of life and side effects are considered as a whole, afatinib offers a considerable additional benefit compared with cisplatin in combination with pemetrexed in the patient group with the EGFR Del19 mutation. The classification of the extent as ‘considerable’ stems in particular from the moderate prolongation of overall survival. Furthermore, there are predominantly positive effects in terms of symptoms, as well as a positive effect on quality of life (endpoint ‘physical functioning’). A classification of the extent as ‘major’ is not justified, not least because the treatment does not achieve a cure of the disease, long-term freedom from serious symptoms or the widespread avoidance of serious side effects.
  • The probability of additional benefit is classified as an indication. In this assessment, account is taken, on the one hand, of the minor potential for bias regarding the overall survival endpoint, but, on the other hand, also of the high potential for bias regarding the endpoints relating to symptoms and side effects, as well as the fact that only one study suitable for the benefit assessment is available.

1b) Previously untreated patients with an ECOG performance status of 0 or 1: patient group with the EGFR L858R mutation

• For previously untreated patients with an ECOG performance status of 0 or 1 and the EGFR mutation L858R, there is a hint of a minor additional benefit compared with the appropriate comparator therapy, cisplatin in combination with pemetrexed.
• The G-BA classifies the extent of the additional benefit of afatinib as minor, based on the criteria in Section 5(7) of the AM-NutzenV, taking into account the severity of the disease and the therapeutic objective in the treatment of the disease. Compared with the appropriate comparator therapy of cisplatin in combination with pemetrexed, there is, in accordance with Section 5(7) in conjunction with § 2(3) of the AM-NutzenV, this represents a moderate – and not merely minor – improvement in the therapy-relevant benefit, as a reduction in non-serious symptoms is achieved.
• Due to the high potential for bias in the endpoints relating to symptoms and side effects, the probability of additional benefit is classified as a hint.
• mortality
  • Subgroup effects were observed for both data sets depending on EGFR mutation status (Del19, L858R, other mutations) (interaction tests: 1st data set: p = 0.033; 2nd data set: p = 0.002). The results from these patient populations are therefore used to assess the additional benefit.
  • In the patient population with the L858R EGFR mutation, there were no statistically significant differences between the treatment arms.
• Morbidity – Progression-free survival (PFS)
  • In the patient populations of patients with the EGFR L858R mutation or other EGFR mutations, there were no statistically significant differences between the treatment arms.
• Morbidity – Dyspnoea
  • Subgroup effects were observed between patients with either an EGFR Del19 mutation or an EGFR L858R mutation (EGFR Del19/L858R patient population) and patients with other EGFR mutations.
  • In the EGFR Del19/L858R patient population, the proportion of patients with an improvement in symptoms was 42.6% in the intervention arm versus 21.9% in the control arm (QLQ-LC13; p = 0.002), and 45.6% in the intervention arm versus 27.1% in the control arm (QLQ-C30; p = 0.005). The proportion of patients with a worsening of symptoms was 47.1% in the intervention arm versus 58.7% in the control arm (QLQ-LC13; p < 0.001), and 33.3% in the intervention arm versus 50% in the control arm (QLQ-C30; p < 0.001).
• Morbidity – Cough
  • For the endpoint of cough, statistically significant differences in favour of afatinib were observed in the overall population. An improvement in symptoms was observed in 55.5% of patients in the intervention arm versus 36.2% of patients in the control arm (p = 0.003).
• Morbidity – pain (arm/shoulder)
  • For the endpoint of pain (arm/shoulder), a statistically significant difference in favour of afatinib was observed in the overall population: An improvement in symptoms was observed in 30.3% of patients in the intervention arm compared with 17.8% of patients in the control arm (p = 0.022).
• Morbidity – pain (chest)
  • For the endpoint ‘pain (chest)’, a statistically significant difference in favour of afatinib was observed in the overall population: The proportion of patients experiencing a worsening of symptoms was 34.3% in the intervention arm versus 39.1% in the control arm (p = 0.023).
• Morbidity – Hair loss
  • For the endpoint of hair loss, a statistically significant result in favour of afatinib was observed in the overall population: the time to worsening of symptoms was 3.5 months in the intervention arm versus 1.7 months in the control arm (p < 0.001).
• Morbidity – Fatigue
  • For the endpoint of fatigue, a statistically significant difference in favour of afatinib was observed in the overall population: The proportion of patients experiencing a worsening of symptoms was 63.5% in the intervention arm versus 69.6% in the control arm, and the median time to worsening was 3 months in the intervention arm versus 1.7 months in the control arm (p = 0.009).
  • In the patient populations of patients with the L858R EGFR mutation or other EGFR mutations, no statistically significant differences were observed between the treatment arms for the endpoint of fatigue.
• Quality of life – Physical functioning (EORTC QLQ-C30)
  • In the patient populations with the L858R EGFR mutation or other EGFR mutations, there were no statistically significant differences between the treatment arms for the endpoint of physical functioning.
• Side effects
  • The desired effects of afatinib are accompanied by adverse events (AEs). However, a comparison of side effects between the study arms is complicated by significant differences in the duration of follow-up.
  • Based on the unadjusted proportions, there were no significant differences between the study arms in the proportions of patients experiencing at least one adverse event, at least one serious adverse event, at least one AE of CTCAE grade 3 or 4, or at least one adverse event leading to discontinuation of the study.
  • With regard to common severe side effects (side effects of CTCAE grade ≥ 3 occurring in ≥ 5 % of patients in at least one study arm), different treatment-specific patterns were observed in the side effect profiles between the two treatment groups. Minor rates were observed in the intervention arm compared with the control arm for fatigue (2.2% versus 9.9%), neutropenia (0.9% versus 16.2%) and leucopenia (0.4% versus 8.1%). Higher rates in the intervention arm compared with the control arm were observed for diarrhoea (14.8% versus 1.8%), rash (13.1% versus 0%) and nail changes (11.4% versus 0%).
  • Overall, with regard to the assessment of additional benefit, the side effects do not indicate either an advantage or a disadvantage for afatinib.
• Conclusion
  • When the results on mortality, morbidity, quality of life and side effects are considered as a whole, afatinib offers a minor additional benefit compared with cisplatin in combination with pemetrexed in the patient group with the L858R EGFR mutation. The classification of the extent as ‘minor’ takes into account that, when weighing up the effects on symptoms, the positive effects predominate, although the symptoms present are not considered to be serious. Furthermore, there was no prolongation of overall survival and no improvement in quality of life.

1c) Previously untreated patients with an ECOG performance status of 0 or 1: patient group with other EGFR mutations

• For previously untreated patients with an ECOG performance status of 0 or 1 and other EGFR mutations, there is an indication for less benefit compared with the appropriate comparator therapy, cisplatin in combination with pemetrexed.
• On the basis of the criteria set out in Section 5(7) of the AM-NutzenV, taking into account the severity of the disease and the therapeutic objective in treating the disease, the G-BA assesses the benefit of afatinib as less than that of the appropriate comparator therapy. Compared with the appropriate comparator therapy of cisplatin in combination with pemetrexed, there is, in accordance with Section 5(7) in conjunction with Section 2(3) of the AM-NutzenV, less benefit, as a reduction in survival duration (endpoint: overall survival) has been observed.
• The probability is classified as an indication.
• mortality
  • Subgroup effects depending on EGFR mutation status (Del19, L858R, other mutations) were observed for both data cuts (interaction tests: 1st data cut: p = 0.033; 2nd data cut-off: p = 0.002). The results from these patient populations are therefore used to assess the additional benefit.
  • In the patient population with ‘other EGFR mutations’, however, a statistically significant difference was observed to the detriment of afatinib (HR 3.08, 95% CI [1.04; 9.15]; p = 0.034).
  • The patient population of patients with ‘other EGFR mutations’ comprises a small patient population from the LUX-Lung 3 study (26 patients in the intervention arm and 11 patients in the control arm) with various types of EGFR mutations. Furthermore, there is an uneven distribution of individual mutations between the treatment arms.
• Morbidity – Progression-free survival (PFS)
  • In the patient populations of patients with the L858R EGFR mutation or other EGFR mutations, no statistically significant differences were observed between the treatment arms.
• Morbidity – Dyspnoea
  • Subgroup effects were observed between patients with either an EGFR Del19 mutation or an EGFR L858R mutation (EGFR Del19/L858R patient population) and patients with other EGFR mutations.
  • In the patient population with other EGFR mutations, there were no statistically significant differences between the treatment arms for the endpoint of dyspnoea.
• Morbidity – Fatigue
  • In the patient populations of patients with the EGFR L858R mutation or other EGFR mutations, there were no statistically significant differences between the treatment arms for the endpoint of fatigue.
• Quality of life – Physical functioning (EORTC QLQ-C30)
  • In the patient populations with the EGFR L858R mutation or other EGFR mutations, there were no statistically significant differences between the treatment arms for the endpoint of physical functioning.
• Side effects
  • The desired effects of afatinib are accompanied by adverse events (AEs). However, a comparison of side effects between the study arms is complicated by significant differences in the duration of follow-up.
  • Based on the unadjusted proportions, there were no significant differences between the study arms in the proportions of patients experiencing at least one adverse event, at least one serious adverse event, at least one AE of CTCAE grade 3 or 4, or at least one adverse event leading to discontinuation of the study.
  • With regard to common severe side effects (side effects with a CTCAE grade of ≥ 3 occurring in ≥ 5 % of patients in at least one study arm), different treatment-specific patterns emerged in the side effect profile between the two treatment groups. Minor rates were observed in the intervention arm compared with the control arm for fatigue (2.2% versus 9.9%), neutropenia (0.9% versus 16.2%) and leucopenia (0.4% versus 8.1%). Higher rates in the intervention arm compared with the control arm were observed for diarrhoea (14.8% versus 1.8%), rash (13.1% versus 0%) and nail changes (11.4% versus 0%).
  • Overall, with regard to the assessment of additional benefit, the side effects do not indicate either an advantage or a disadvantage for afatinib.
• Conclusion
  • When the results on mortality, morbidity, quality of life and side effects are considered as a whole, afatinib offers less benefit compared with cisplatin in combination with pemetrexed in the patient group with other EGFR mutations. This classification takes into account the reduction in overall survival in the patient group with other EGFR mutations. Owing to the different mutations within the patient population, it cannot be ruled out that results with differing directions of effect may exist for various individual mutations.
  • The probability is classified as an indication. This takes into account, on the one hand, the minor potential for bias regarding the endpoint of overall survival and, on the other hand, the fact that only one study suitable for benefit assessment is available.

2) Previously untreated patients with an ECOG performance status of 2

• For untreated patients with an ECOG performance status of 2, additional benefit is not proven.
• Reasoning: No study was submitted that would have been suitable for assessing the additional benefit compared with the appropriate comparator therapy.

3) Patients who have received one or more courses of chemotherapy

• An additional benefit is not proven for patients who have received one or more courses of chemotherapy.
• Reason: No study was submitted that would have been suitable for assessing the additional benefit compared with the appropriate comparator therapy.

Courtesy translation only, please refer to the German original.